Transcriptional activation through specific cis-acting elements such as the antioxidant response element (ARE) is important for expression of various cytoprotective genes. Members of the CNC subfamily of basic-leucine zipper transcription factors including Nrf1 and Nrf2 have been implicated to mediate ARE function. In particular, Nrf2 has been shown to coordinate expression of antioxidant and phase 2 metabolizing enzymes in response to oxidative stress and xenobiotic exposures, and Nrf2 knockout mice have been shown to suffer from various oxidative stress-induced pathologies. However, there are gaps in our understanding of the role of Nrf1 in oxidative stress response and ARE function in vivo. Nrf1 is highly expressed in neuronal cells, and we have obtained novel evidence that Nrf1 plays a role in neurodegeneration. The extent of this defect and the underlying mechanisms are unknown. We hypothesize that Nrf1 may play a prominent role in regulating cytoprotective genes in this compartment. The long-term goal of our research is to understand the neuroprotective function mediated by the Nrf1 pathway, and its role in neurodegenerative diseases. The immediate goals within this context will be pursued by determining the importance of Nrf1 in stress response in neurons;determining whether Nrf1 is a transcriptional mediator of ARE-regulated genes involved in aspects of neuronal survival and function;and determining the mechanisms of neurodegeneration. The studies outlined here will define the physiologic role of Nrf1 in the brain, and provide basic information regarding neurodegenerative processes that ultimately may provide insights for novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases represent a significant health and economic burden worldwide. Our recent studies suggest that the Nrf1 transcription factor plays a role in neurodegeneration. This proposal focuses on investigating the role of Nrf1 in stress response in neuronal cells and in the pathogenesis of neurodegeneration, and should reveal basic information that is relevant to the pathophysiology and therapy of neurodegenerative diseases.